The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner.
Previous studies have shown that p34(SEI-1), also known as TRIP-Br1, is involved in cell cycle regulations by interacting with a number of important proteins including CDK4. However, the detailed mechanism and structural basis of the interaction remains to be determined. We report the use of in vitro studies to address these problems. First, it was shown that p34(SEI-1) binds to CDK4 directly, and the binding does not compete directly with p16. In the presence of p16, a quaternary complex is formed between p34(SEI-1), CDK4, cyclin D2, and p16. Second, it was found that p34(SEI-1) activates the kinase activity of CDK4 at lower concentrations (reaching the maximum at 500 nM) but inhibits the same activity at higher concentrations, implying that p34(SEI-1)-mediated CDK4 activation is dose-dependent. Again, the effects of p34(SEI-1) and p16 are independent of each other. Third, it was shown that p34(SEI-1) possesses a LexA-mediated transactivation activity. Finally, a set of truncation mutants were used to dissect the structural elements responsible for the different functions of p34(SEI-1). The results indicate that the fragment 30-160 can bind, activate, and inhibit CDK4; the fragment 30-132 can bind and activate but does not inhibit CDK4, while the fragment 30-88 cannot bind, activate, or inhibit but retains the LexA-mediated transactivation activity.


Proteomics of the eukaryotic transcription machinery: identification of proteins associated with components of yeast TFIID by multidimensional mass spectrometry.
The general transcription factor TFIID is a multisubunit complex of TATA-binding protein (TBP) and 14 distinct TBP-associated factors (TAFs). Although TFIID constituents are required for transcription initiation of most mRNA encoding genes, the mechanism of TFIID action remains unclear. To gain insight into TFIID function, we sought to generate a proteomic catalogue of proteins specifically interacting with TFIID subunits. Toward this end, TFIID was systematically immunopurified by using polyclonal antibodies directed against each subunit, and the constellation of TBP- and TAF-associated proteins was directly identified by coupled multidimensional liquid chromatography and tandem mass spectrometry. A number of novel protein-protein associations were observed, and several were characterized in detail. These interactions include association between TBP and the RSC chromatin remodeling complex, the TAF17p-dependent association of the Swi6p transactivator protein with TFIID, and the identification of three novel subunits of the SAGA acetyltransferase complex, including a putative ubiquitin-specific protease component. Our results provide important new insights into the mechanisms of mRNA gene transcription and demonstrate the feasibility of constructing a complete proteomic interaction map of the eukaryotic transcription apparatus.


Chemopreventive effect of PSP through targeting of prostate cancer stem cell-like population.
Recent evidence suggested that prostate cancer stem/progenitor cells (CSC) are responsible for cancer initiation as well as disease progression. Unfortunately, conventional therapies are only effective in targeting the more differentiated cancer cells and spare the CSCs. Here, we report that PSP, an active component extracted from the mushroom Turkey tail (also known as Coriolus versicolor), is effective in targeting prostate CSCs. We found that treatment of the prostate cancer cell line PC-3 with PSP led to the down-regulation of CSC markers (CD133 and CD44) in a time and dose-dependent manner. Meanwhile, PSP treatment not only suppressed the ability of PC-3 cells to form prostaspheres under non-adherent culture conditions, but also inhibited their tumorigenicity in vivo, further proving that PSP can suppress prostate CSC properties. To investigate if the anti-CSC effect of PSP may lead to prostate cancer chemoprevention, transgenic mice (TgMAP) that spontaneously develop prostate tumors were orally fed with PSP for 20 weeks. Whereas 100% of the mice that fed with water only developed prostate tumors at the end of experiment, no tumors could be found in any of the mice fed with PSP, suggesting that PSP treatment can completely inhibit prostate tumor formation. Our results not only demonstrated the intriguing anti-CSC effect of PSP, but also revealed, for the first time, the surprising chemopreventive property of oral PSP consumption against prostate cancer.


Classical versus complex fractional Fourier transformation.
The quantum optical complex fractional Fourier transform (FRFT) has been related to the classical FRFT using both classical and quantum formalisms. In particular, it was shown that the kernel of the complex FRFT can be classically produced with rotated astigmatic optical systems that mimic the quantum entanglement property.


The chromosome 16q region associated with ankylosing spondylitis includes the candidate gene tumour necrosis factor receptor type 1-associated death domain (TRADD).
To replicate and refine the reported association of ankylosing spondylitis (AS) with two non-synonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1. Firstly, 730 independent UK patients with AS were genotyped for rs9939768 and rs6979 and allele frequencies were compared with 2879 previously typed historic disease controls. Secondly, the two data sets were combined in meta-analyses. Finally, 5 tagging SNPs, located between rs9939768 and rs6979, were analysed in 1604 cases and 1020 controls. The association of rs6979 with AS was replicated, p=0.03, OR=1.14 (95% CI 1.01 to 1.28), and a trend for association with rs9939768 detected, p=0.06, OR=1.25 (95% CI 0.99 to 1.57). Meta-analyses revealed association of both SNPs with AS, p=0.0008, OR=1.31 (95% CI 1.12 to 1.54) and p=0.0009, OR=1.15 (95% CI 1.06 to 1.23) for rs9939768 and rs6979, respectively. New associations with rs9033 and rs868213 (p=0.00002, OR=1.23 (95% CI 1.12 to 1.36) and p=0.00002 OR=1.45 (95% CI 1.22 to 1.72), respectively, were identified. The region on chromosome 16 that has been replicated in the present work is interesting as the highly plausible candidate gene, tumour necrosis factor receptor type 1 (TNFR1)-associated death domain (TRADD), is located between rs9033 and rs868213. It will require additional work to identify the primary genetic association(s) with AS.


Trends in adult tobacco use from two South African Demographic and Health Surveys conducted in 1998 and 2003.
Since peaking in the early 1990s in South Africa, tobacco use has declined significantly. The reduction has been attributed to the government's comprehensive tobacco control policies that were introduced at the time. To assess the pattern of tobacco use in the South African Demographic and Health Surveys of 1998 and 2003. Multi-stage sampling was used to select approximately 11 000 households in cross-sectional national surveys. Face-to-face interviews, conducted with 13 826 adults (41% men) aged > or = 15 years in 1998, and 8 115 (42% men) in 2003, included questions on tobacco use according to the WHO STEP-wise surveillance programme. Logistic regression analysis was used to assess the independent effects of selected characteristics on smoking prevalence. Daily or occasional smoking prevalence among women remained unchanged at 10 - 11%; it decreased among men from 42% (1998) to 35% (2003). The decline for men was significant among the poorest and those aged 25 - 44 years. Strong age patterns were observed, peaking at 35 - 44 years, which was reduced among men in 2003. Higher income and education were associated with low prevalence of smoking, while living in urban areas was associated with higher rates. Black men and women smoked significantly less than other population groups. Despite decreased smoking rates in some subgroups, a lapse exists in the efforts to reduce tobacco use, as smoking rates have remained unchanged among women, and also among young adults aged 15 - 24 years.


Combined experimental and computational studies on carbon-carbon reductive elimination from Bis(hydrocarbyl) complexes of (PCP)Ir.
The reductive elimination of carbon-carbon bonds is one of the most fundamentally and synthetically important reaction steps in organometallic chemistry, yet relatively little is understood about the factors that govern the kinetics of this reaction. C-C elimination from complexes with the common d (6) six-coordinate configuration generally proceeds via prior ligand loss, which greatly complicates any attempt to directly measure the rates of the specific elimination step. We report the synthesis of a series of five-coordinate d (6) iridium complexes, ( (tBu)PCP)Ir(R)(R'), where R and R' are Me, Ph, and (phenyl-substituted) vinyl and alkynyl groups. For several of these complexes (R/R' = Ph/Vi, Me/Me, Me/Vi, Me/CCPh, and Vi/CCPh, where Vi = trans-CHCHPh) we have measured the absolute rate of C-C elimination. For R/R' = Ph/Ph, Ph/Me, and Ph/CCPh, we obtain upper limits to the elimination rate; and for R/R' = CCPh/CCPh, a lower limit. In general, the rates decrease (activation barriers increase) according to the following order: acetylide < vinyl approximately Me < Ph. Density functional theory (DFT) calculations offer significant insight into the factors behind this order, in particular the slow rates for elimination of the vinyl and, especially, phenyl complexes. The transition states are calculated to involve rotation of the aryl or vinyl group around the Ir-C bond, prior to C-C elimination, such that the group to which it couples can add to the face of the aryl or vinyl group. This rotation is severely hindered by the presence of the phosphino -t-butyl groups that lie above and below the plane of the aryl/vinyl group in the ground state. Accordingly, calculations predict dramatically different relative rates of elimination from the much less sterically hindered complexes ( (H)PCP)Ir(R)(R'). For example, the barrier to elimination from ( (H)PCP)Ir(Me) 2 is 20 kcal/mol, which is 2 kcal/mol greater than from the ( (tBu)PCP)Ir analogue. In contrast, the activation enthalpies calculated for vinyl-vinyl and phenyl-phenyl elimination from ( (H)PCP)Ir are remarkably low, only 2 and 9 kcal/mol, respectively; these values are 16 and 22 kcal/mol less than those of the corresponding ( (tBu)PCP)Ir complexes. Moreover, since these eliminations are very nearly thermoneutral, the barriers are calculated to be equally low for the reverse reactions [C-C oxidative addition to ( (H)PCP)Ir]. The absence of differences in intraligand CC bond lengths in the transition states relative to the ground states, combined with a comparison of calculated "face-on" and "planar" transition states for C-C coupling, suggests that the critical importance of the aryl/vinyl rotation is based on geometric or steric factors rather than electronic ones. Thus there is no evidence for participation of the pi or pi* orbitals of the aryl or vinyl groups in the formation of the C-C bond, although a small pi effect cannot be rigorously excluded. Likewise, the results do not support the hypothesis that the degree of directionality of the carbon-based orbital used for bonding to iridium (sp (3) > sp (2) > sp) plays an important role in this system in determining the barrier to reductive elimination.


Soybean extracts increase cell surface ZIP4 abundance and cellular zinc levels: a potential novel strategy to enhance zinc absorption by ZIP4 targeting.
Dietary zinc deficiency puts human health at risk, so we explored strategies for enhancing zinc absorption. In the small intestine, the zinc transporter ZIP4 functions as an essential component of zinc absorption. Overexpression of ZIP4 protein increases zinc uptake and thereby cellular zinc levels, suggesting that food components with the ability to increase ZIP4 could potentially enhance zinc absorption via the intestine. In the present study, we used mouse Hepa cells, which regulate mouse Zip4 (mZip4) in a manner indistinguishable from that in intestinal enterocytes, to screen for suitable food components that can increase the abundance of ZIP4. Using this ZIP4-targeting strategy, two such soybean extracts were identified that were specifically able to decrease mZip4 endocytosis in response to zinc. These soybean extracts also effectively increased the abundance of apically localized mZip4 in transfected polarized Caco2 and Madin-Darby canine kidney cells and, moreover, two apically localized mZip4 acrodermatitis enteropathica mutants. Soybean components were purified from one extract and soyasaponin Bb was identified as an active component that increased both mZip4 protein abundance and zinc levels in Hepa cells. Finally, we confirmed that soyasaponin Bb is capable of enhancing cell surface endogenous human ZIP4 in human cells. Our results suggest that ZIP4 targeting may represent a new strategy to improve zinc absorption in humans.


Gender Differences in Mental Health Outcomes before, during, and after the Great Recession.
We examined gender differences in mental health outcomes during and post-recession versus pre-recession. We utilized 2005-2006, 2008-2009, and 2010-2011 data from the Medical Expenditure Panel Survey. Females had lower odds of depression diagnoses during and post-recession and better mental health during the recession, but higher odds of anxiety diagnoses post-recession. Males had lower odds of depression diagnoses and better mental health during and post-recession and lower Kessler 6 scores post-recession. We conducted stratified analyses, which confirmed that the aforementioned findings were consistent across the four different regions of the U.S., by employment status, income and health care utilization. Importantly, we found that the higher odds of anxiety diagnoses among females after the recession were mainly prominent among specific subgroups of females: those who lived in the Northeast or the Midwest, the unemployed, and those with low household income. Gender differences in mental health in association with the economic recession highlight the importance of policymakers taking these differences into consideration when designing economic and social policies to address economic downturns. Future research should examine the reasons behind the decreased depression diagnoses among both genders, and whether they signify decreased mental healthcare utilization or increased social support and more time for exercise and leisure activities.


Intermediate tree cover can maximize groundwater recharge in the seasonally dry tropics.
Water scarcity contributes to the poverty of around one-third of the world's people. Despite many benefits, tree planting in dry regions is often discouraged by concerns that trees reduce water availability. Yet relevant studies from the tropics are scarce, and the impacts of intermediate tree cover remain unexplored. We developed and tested an optimum tree cover theory in which groundwater recharge is maximized at an intermediate tree density. Below this optimal tree density the benefits from any additional trees on water percolation exceed their extra water use, leading to increased groundwater recharge, while above the optimum the opposite occurs. Our results, based on groundwater budgets calibrated with measurements of drainage and transpiration in a cultivated woodland in West Africa, demonstrate that groundwater recharge was maximised at intermediate tree densities. In contrast to the prevailing view, we therefore find that moderate tree cover can increase groundwater recharge, and that tree planting and various tree management options can improve groundwater resources. We evaluate the necessary conditions for these results to hold and suggest that they are likely to be common in the seasonally dry tropics, offering potential for widespread tree establishment and increased benefits for hundreds of millions of people.


A comparison of course-related stressors in undergraduate problem-based learning (PBL) versus non-PBL medical programmes.
Medical students report high levels of stress related to their medical training as well as to other personal and financial factors. The aim of this study is to investigate whether there are differences in course-related stressors reported by medical students on undergraduate problem-based learning (PBL) and non-PBL programmes in the UK. A cross-sectional study of second-year medical students in two UK medical schools (one PBL and one non-PBL programme) was conducted. A 16-question self-report questionnaire, derived from the Perceived Medical Student Stress Scale and the Higher Education Stress Inventory, was used to measure course-related stressors. Following univariate analysis of each stressor between groups, multivariate logistic regression was used to determine which stressors were the best predictors of each course type, while controlling for socio-demographic differences between the groups. A total of 280 students responded. Compared to the non-PBL students (N = 197), the PBL students (N = 83) were significantly more likely to agree that: they did not know what the faculty expected of them (Odds Ratio (OR) = 0.38, p = 0.03); there were too many small group sessions facilitated only by students resulting in an unclear curriculum (OR = 0.04, p < 0.0001); and that there was a lack of opportunity to explore academic subjects of interest (OR = 0.40, p = 0.02). They were significantly more likely to disagree that: there was a lack of encouragement from teachers (OR = 3.11, p = 0.02); and that the medical course fostered a sense of anonymity and feelings of isolation amongst students (OR = 3.42, p = 0.008). There are significant differences in the perceived course-related stressors affecting medical students on PBL and non-PBL programmes. Course designers and student support services should therefore tailor their work to minimise, or help students cope with, the specific stressors on each course type to ensure optimum learning and wellbeing among our future doctors.


Fat flies expanded the hippo pathway: a matter of size control.
By simultaneously inhibiting cell proliferation while promoting apoptosis, the Hippo signaling pathway provides a robust mechanism to restrict organ size during Drosophila development. Despite impressive progress in revealing the key intracellular components of this growth-regulatory pathway, the nature of the signal that regulates Hippo signaling in vivo has remained elusive. Several studies now implicate the atypical cadherin protein Fat as a cell surface receptor for the Hippo signaling pathway, thus potentially linking the Hippo kinase cascade with the extracellular milieu.


Suppression of enhanced physiological tremor via stochastic noise: initial observations.
Enhanced physiological tremor is a disabling condition that arises because of unstable interactions between central tremor generators and the biomechanics of the spinal stretch reflex. Previous work has shown that peripheral input may push the tremor-related spinal and cortical systems closer to anti-phase firing, potentially leading to a reduction in tremor through phase cancellation. The aim of the present study was to investigate whether peripherally applied mechanical stochastic noise can attenuate enhanced physiological tremor and improve motor performance. Eight subjects with enhanced physiological tremor performed a visuomotor task requiring the right index finger to compensate a static force generated by a manipulandum to which Gaussian noise (3-35 Hz) was applied. The finger position was displayed on-line on a monitor as a small white dot which the subjects had to maintain in the center of a larger green circle. Electromyogram (EMG) from the active hand muscles and finger position were recorded. Performance was measured by the mean absolute deviation of the white dot from the zero position. Tremor was identified by the acceleration in the frequency range 7-12 Hz. Two different conditions were compared: with and without superimposed noise at optimal amplitude (determined at the beginning of the experiment). The application of optimum noise reduced tremor (accelerometric amplitude and EMG activity) and improved the motor performance (reduced mean absolute deviation from zero). These data provide the first evidence of a significant reduction of enhanced physiological tremor in the human sensorimotor system due to application of external stochastic noise.


Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.
Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .).


Effects of carboxymethyl cellulose-based saliva substitutes with varying degrees of saturation with respect to calcium phosphates on artificial enamel lesions.
The aim of the present study was to evaluate the effects of experimental saliva substitutes based on carboxymethyl cellulose (CMC) differing in degrees of saturation with respect to calcium phosphates on the mineral loss of enamel in vitro. Demineralized bovine specimens (subsurface lesions) were exposed to one of six experimental CMC-based solutions with theoretical degrees of saturation with respect to octacalcium phosphate (S(OCP)) of S0, S0.5, S1, S2, S4, and S8 for 10 weeks. A previously studied saliva substitute (Glandosane) and two aqueous solutions (C0 and C1) served as controls. Mineral losses and lesion depths before and after storage were evaluated from microradiographs. Free and bound calcium as well as phosphate and fluoride concentrations were determined. According to these measurements, S(OCP) of S2, S4, and S8 was 0.3, 1.1, and 3.4, respectively. Storage in Glandosane and both negative controls resulted in significant demineralization (p < 0.05). Only S2 significantly remineralized the specimens (p < 0.05). All other solutions showed neutral effects. No significant differences in mineralization between S0 and C0 as well as between S1 and C1 could be observed (p > 0.05). It can be concluded that a CMC-based solution actually unsaturated with respect to octacalcium phosphate (S2) shows most pronounced remineralization capability under the conditions chosen. This might be explained by a more favorable balance between calcium bound to CMC in an adsorbed layer at the enamel-liquid interface and heterogeneous nucleation of calcium phosphates within a solution compared to solutions either supersaturated or having lower levels of saturation.


Rapid profiling of enteric coated drug delivery spheres via broadband acoustic resonance dissolution spectroscopy (BARDS).
There is an increased trend towards the use of drug and enteric coated sugar spheres for controlled oral delivery of active pharmaceutical ingredients (API). This trend is driven by increased efficacy and ease of formulation of different dosage levels. However, difficulties exist in determining the thickness of drug and enteric coatings in a time efficient manner during manufacture, quality assurance and stability testing. The thickness of the coating determines the dosage of the API and the thickness of the enteric coating determines the release rate of the drug in the gastro-intestinal tract. Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) offers a rapid new approach to characterising the enteric coating thickness and the raw materials used in their manufacture. BARDS applications are based on reproducible changes in the compressibility of a solvent during dissolution which is monitored acoustically due to associated changes in the speed of sound in solution. It is demonstrated how core delivery sugar spheres have unique acoustic spectra attributable to the mean size distribution of the spheres. A steady state acoustic lag time is associated with the disintegration of the enteric coating, in basic solution. This lag time can be manipulated by varying the concentration of the base which affects the rate at which the coating dissolves. It is anticipated that the thickness/loading of the spheres can be estimated from the lag time.


Eosinophilic Gastroenteritis Presenting As Unexplained Chronic Abdominal Pain.
A 27-year-old Caucasian female was hospitalized three times over a four-month period for recurrent, intermittent abdominal pain associated with nausea and diarrhea. No signs or symptoms of gastrointestinal (GI) bleeding were present. A stool occult blood test and stool enteric pathogen tests were negative. A complete blood count (CBC) revealed a peripheral blood eosinophil count of 1080 cells /µL without any inflammatory reaction. An upper endoscopy showed grossly normal-appearing esophageal and duodenal mucosa; however, a gastric mucosal biopsy showed an eosinophil infiltration of ≥20 eosinophils/high power field (HPF). Based on these findings, she was diagnosed with eosinophilic gastroenteritis (EGE). A definitive diagnosis of EGE should be confirmed with both an analysis of gastrointestinal mucosal biopsy and an elevated peripheral blood eosinophil count. Specifically, histological evaluation of the mucosal tissue must show an eosinophilic infiltration rate of 20 eosinophils/HPF. The diagnosis should be followed by an extensive review of the patient's allergic disease history.


Vaccination against GIP for the treatment of obesity.
According to the WHO, more than 1 billion people worldwide are overweight and at risk of developing chronic illnesses, including cardiovascular disease, type 2 diabetes, hypertension and stroke. Current therapies show limited efficacy and are often associated with unpleasant side-effect profiles, hence there is a medical need for new therapeutic interventions in the field of obesity. Gastric inhibitory peptide (GIP, also known as glucose-dependent insulinotropic polypeptide) has recently been postulated to link over-nutrition with obesity. In fact GIP receptor-deficient mice (GIPR(-/-)) were shown to be completely protected from diet-induced obesity. Thus, disrupting GIP signaling represents a promising novel therapeutic strategy for the treatment of obesity. In order to block GIP signaling we chose an active vaccination approach using GIP peptides covalently attached to virus-like particles (VLP-GIP). Vaccination of mice with VLP-GIP induced high titers of specific antibodies and efficiently reduced body weight gain in animals fed a high fat diet. The reduction in body weight gain could be attributed to reduced accumulation of fat. Moreover, increased weight loss was observed in obese mice vaccinated with VLP-GIP. Importantly, despite the incretin action of GIP, VLP-GIP-treated mice did not show signs of glucose intolerance. This study shows that vaccination against GIP was safe and effective. Thus active vaccination may represent a novel, long-lasting treatment for obesity. However further preclinical safety/toxicology studies will be required before the therapeutic concept can be addressed in humans.


Ontogeny of adrenal steroid biosynthesis: why girls will be girls.
Male and female external genitalia appear identical early in gestation. Testosterone exposure at 8-12 weeks' gestation causes male differentiation. Female fetuses virilize if their adrenals secrete excessive levels of androgens, as occurs in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. This can be ameliorated by administering dexamethasone to the mother. A study by Goto et al. in this issue of the JCI provides a rationale for this treatment by demonstrating that the fetal hypothalamic-pituitary-adrenal axis is fully functional when the genitalia differentiate (see the related article beginning on page 953). Dexamethasone suppresses this axis, reducing abnormal secretion of adrenal androgens. Their results also show that cortisol synthesis by the fetal adrenal decreases after this period, allowing the adrenal to secrete high levels of dehydroepiandrosterone, an androgen precursor. However, this does not virilize female fetuses because androgens are aromatized to estrogens in the placenta. Thus normal sexual differentiation requires exquisite timing of fetal cortisol and androgen secretion versus placental capacity for aromatization.


Sildenafil Prevents Apoptosis of Human First-Trimester Trophoblast Cells Exposed to Oxidative Stress: Possible Role for Nitric Oxide Activation of 3',5'-cyclic Guanosine Monophosphate Signaling.
Human first-trimester trophoblast cells proliferate at low O2, but survival is compromised by oxidative stress, leading to uteroplacental insufficiency. The vasoactive drug, sildenafil citrate (Viagra, Sigma, St Louis, Missouri), has proven useful in reducing adverse pregnancy outcomes. An important biological function of this pharmaceutical is its action as an inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 activity, which suggests that it could have beneficial effects on trophoblast survival. To investigate whether sildenafil can prevent trophoblast cell death, human first-trimester villous explants and the HTR-8/SVneo cytotrophoblast cell line were exposed to hypoxia and reoxygenation (H/R) to generate oxidative stress, which induces apoptosis. Apoptosis was optimally inhibited during H/R by 350 ng/mL sildenafil. Sildenafil-mediated survival was reversed by l-N(G)-nitro-l-arginine methyl ester hydrochloride or cGMP antagonist, indicating a dependence on both nitric oxide (NO) and cGMP. Indeed, either a cGMP agonist or an NO generator was cytoprotective independent of sildenafil. These findings suggest a novel intervention route for patients with recurrent pregnancy loss or obstetrical placental disorders.


Plasticity of noddy parents and offspring to sea-surface temperature anomalies.
Behavioral and/or developmental plasticity is crucial for resisting the impacts of environmental stressors. We investigated the plasticity of adult foraging behavior and chick development in an offshore foraging seabird, the black noddy (Anous minutus), during two breeding seasons. The first season had anomalously high sea-surface temperatures and 'low' prey availability, while the second was a season of below average sea-surface temperatures and 'normal' food availability. During the second season, supplementary feeding of chicks was used to manipulate offspring nutritional status in order to mimic conditions of high prey availability. When sea-surface temperatures were hotter than average, provisioning rates were significantly and negatively impacted at the day-to-day scale. Adults fed chicks during this low-food season smaller meals but at the same rate as chicks in the unfed treatment the following season. Supplementary feeding of chicks during the second season also resulted in delivery of smaller meals by adults, but did not influence feeding rate. Chick begging and parental responses to cessation of food supplementation suggested smaller meals fed to artificially supplemented chicks resulted from a decrease in chick demands associated with satiation, rather than adult behavioral responses to chick condition. During periods of low prey abundance, chicks maintained structural growth while sacrificing body condition and were unable to take advantage of periods of high prey abundance by increasing growth rates. These results suggest that this species expresses limited plasticity in provisioning behavior and offspring development. Consequently, responses to future changes in sea-surface temperature and other environmental variation may be limited.


Real-time 4-D radiotherapy for lung cancer.
Respiratory motion considerably influences dose distribution, and thus clinical outcomes in radiotherapy for lung cancer. Breath holding, breath coaching, respiratory gating with external surrogates, and mathematical predicting models all have inevitable uncertainty due to the unpredictable variations of internal tumor motion. The amplitude of the same tumor can vary with standard deviations > 5 mm occurring in 23% of T1-2N0M0 non-small cell lung cancers. Residual motion varied 1-6 mm (95th percentile) for the 40% duty cycle of respiratory gating with external surrogates. The 4-D computed tomography is vulnerable to problems relating to the external surrogates. Real-time 4-D radiotherapy (4DRT), where the temporal changes in anatomy during the delivery of radiotherapy are explicitly considered in real time, is emerging as a new method to reduce these known sources of uncertainty. Fluoroscopic, real-time tumor-tracking technology using internal fiducial markers near the tumor has ± 2 mm accuracy, and has achieved promising clinical results when used with X-ray therapy. Instantaneous irradiation based on real-time verification of internal fiducial markers is considered the minimal requisite for real-time 4DRT of lung cancers at present. Real-time tracking radiotherapy using gamma rays from positron emitters in tumors is in the preclinical research stage, but has been successful in experiments in small animals. Real-time tumor tracking via spot-scanning proton beam therapy has the capability to cure large lung cancers in motion, and is expected to be the next-generation real-time 4DRT.


First observations of the fourth generation synthetic halocarbons HFC-1234yf, HFC-1234ze(E), and HCFC-1233zd(E) in the atmosphere.
Halogenated alkenes are a class of anthropogenic substances, which replace ozone-depleting substances and long-lived greenhouse gases in the foam-blowing, refrigeration, and solvent sectors. We report the first multiyear atmospheric measurements of the hydrofluorocarbons HFC-1234yf (2,3,3,3-tetrafluoroprop-1-ene, CF3CF═CH2), and HFC-1234ze(E) (E-1,3,3,3-tetrafluoroprop-1-ene trans-CF3CH═CHF), and the hydrochlorofluorocarbon HCFC-1233zd(E) (E-1-chloro-3,3,3-trifluoroprop-1-ene trans-CF3CH═CHCl) from the high altitude observatory at Jungfraujoch and from urban Dubendorf (Switzerland). When observations started in 2011 HFC-1234yf was undetectable at Jungfraujoch (mole fractions <0.003 ppt, parts-per-trillion, 10(-12)) but since then the percentage of measurements with detectable mole fractions has steadily increased to 4.5% in 2014. By contrast, in 2014 HFC-1234ze(E) was detectable in half of our samples at Jungfraujoch and in all samples at Dubendorf demonstrating the wide use of this compound within the air mass footprints of the stations. Our back trajectory analysis for the Jungfraujoch observations suggests high emission strength of HFC-1234ze(E) in the Belgium/Netherlands region. HCFC-1233zd(E) is present at very low mole fractions (typically <0.03 ppt) at both stations, and features pronounced seasonality and a general absence of pollution events during our 2013-2014 measurements. This is indicative of the presence of significant emissions from source locations outside the footprints of the two stations. Based on a simple one-box model calculation we estimate globally increasing HCFC-1233zd(E) emissions from 0.2 Gg yr(-1) in 2013 to 0.5 Gg yr(-1) for 2014.


The effects of shell layer morphology and processing on the electrical and photovoltaic properties of silicon nanowire radial p+ - n+ junctions.
Single wire p(+)-n(+) radial junction nanowire solar cell devices were fabricated by low pressure chemical vapor deposition of n(+) silicon shell layers on p(+) silicon nanowires synthesized by vapor-liquid-solid growth. The n(+)-shell layers were deposited at two growth temperatures (650 °C and 950 °C) to study the impact of shell crystallinity on the device properties. The n-type Si shell layers deposited at 650 °C were polycrystalline and resulted in diodes that were not rectifying. A pre-coating anneal at 950 °C in H2 improved the structural quality of the shell layers and yielded diodes with a dark saturation current density of 3 × 10(-5) A cm(-2). Deposition of the n-type Si shell layer at 950 °C resulted in epitaxial growth on the nanowire core, which lowered the dark saturation current density to 3 × 10(-7) A cm(-2) and increased the solar energy conversion efficiency. Temperature-dependent current-voltage measurements demonstrated that the 950 °C coated devices were abrupt junction p(+)-n(+) diodes with band-to-band tunneling at high reverse-bias voltage, while multi-step tunneling degraded the performance of devices fabricated with a 950 °C anneal and 650 °C coating. The higher trap density of the 950 °C annealed 650 °C coated devices is believed to arise from the polycrystalline nature of the shell layer coating, which results in an increased density of dangling bonds at the p(+)-n(+) junction interface.


Coffee consumption is positively related to insulin secretion in the Shanghai High-Risk Diabetic Screen (SHiDS) Study.
It has been proved that coffee consumption was associated with a lower risk of type 2 diabetes mellitus. But the benefit effect of coffee on hyperglycemia in Chinese population was largely unknown. Besides, the relationship of coffee intake and diabetic pathogenesis was still unclear. The study population was selected from the Shanghai High-Risk Diabetic Screen (SHiDS) project. A total of 1328 individuals over 18 years of age who have the information of coffee intake were enrolled in the study from 2012 to 2016. Each participant finished a five-point 75 g oral glucose tolerance test and finished a standard questionnaire. Insulin resistance was evaluated by HOMA-IR and insulin secretion was evaluated by HOMA-β, Stumvoll first phase and second phase indexes. Coffee consumption group had lower plasma glucose levels at 2-h and 3-h and higher insulin levels at fasting, 30-min and 1-h during OGTT after adjustment with age, fat%, BMI, waist, tea intake, smoking habit, alcohol intake, diabetes family history and educational status (P for PG2h = 0.002; P for PG3h = 0.010; P for FIN = 0.010; P for IN30min = 0.001; P for IN1h = 0.002). Both HOMA-β and Stumvoll formula indexes were positively related to coffee consumption (P for HOMA-β = 0.033; P for Stumvoll first phase = 0.003; P for Stumvoll second phase = 0.001). Logistic regression analysis further confirmed that coffee intake was independently associated with higher levels of HOMA-β and Stumvoll insulin secretion indexes [OR (95% CI) for HOMA-β = 2.270 (1.456-3.538); OR (95% CI) for Stumvoll first phase = 2.071 (1.352-3.173); OR (95% CI) for Stumvoll second phase = 1.914 (1.260-2.906)]. Coffee intake is independently and positively related to pancreatic beta cell function in a large high-risk diabetic Chinese population.


IFNgamma and TNFalpha account for a pro-clonogenic activity secreted by activated murine peritoneal macrophages.
In the present study, we found that murine peritoneal macrophages elicited by BCG or Listeria monocytogenes release into the media an activity capable of stimulating the lung colonization as well as the expression of MHC class I antigens in B16 melanoma cells. A similar activity has previously been found in media conditioned by Corynebacterium parvum-elicited macrophages. Analysis by gel filtration chromatography of media conditioned by Corynebacterium parvum-, BCG- or Listeria monocytogenes-elicited macrophages revealed that the material responsible for the pro-clonogenic activity concentrated in chromatographic fractions corresponding to molecular weights (25 to 52 kDa) which are characteristic of certain cytokines. Thus, we challenged the various macrophage-conditioned media with polyclonal antibodies against IFNgamma and TNFalpha, and found that the macrophage pro-clonogenic activity was completely abolished in the presence of anti-IFNgamma antibodies, but only partially inhibited by anti-TNFalpha antibodies. This finding suggests a cooperative participation of the two cytokines to the pro-clonogenic activity of the media conditioned by Corynebacterium parvum-, BCG- or Listeria monocytogenes-elicited macrophages.


The Effect of the ZrO2 Loading in SiO2@ZrO2-CaO Catalysts for Transesterification Reaction.
The effect of the ZrO2 loading was studied on spherical SiO2@ZrO2-CaO structures synthetized by a simple route that combines the Stöber and sol-gel methods. The texture of these materials was determined using SBET by N2 adsorption, where the increment in SiO2 spheres' surface areas was reached with the incorporation of ZrO2. Combined the characterization techniques of using different alcoholic dissolutions of zirconium (VI) butoxide 0.04 M, 0.06 M, and 0.08 M, we obtained SiO2@ZrO2 materials with 5.7, 20.2, and 25.2 wt % of Zr. Transmission electron microscopy (TEM) analysis also uncovered the shape and reproducibility of the SiO2 spheres. The presence of Zr and Ca in the core-shell was also determined by TEM. X-ray diffraction (XRD) profiles showed that the c-ZrO2 phase changed in to m-ZrO2 by incorporating calcium, which was confirmed by Raman spectroscopy. The purity of the SiO2 spheres, as well as the presence of Zr and Ca in the core-shell, was assessed by the Fourier transform infrared (FTIR) method. CO2 temperature programmed desorption (TPD-CO2) measurements confirmed the increment in the amount of the basic sites and strength of these basic sites due to calcium incorporation. The catalyst reuse in FAME production from canola oil transesterification allowed confirmation that these calcium core@shell catalysts turn out to be actives and stables for this reaction.


Quantitative analysis of ruminal bacterial populations involved in lipid metabolism in dairy cows fed different vegetable oils.
Vegetable oils are used to increase energy density of dairy cow diets, although they can provoke changes in rumen bacteria populations and have repercussions on the biohydrogenation process. The aim of this study was to evaluate the effect of two sources of dietary lipids: soybean oil (SO, an unsaturated source) and hydrogenated palm oil (HPO, a saturated source) on bacterial populations and the fatty acid profile of ruminal digesta. Three non-lactating Holstein cows fitted with ruminal cannulae were used in a 3×3 Latin square design with three periods consisting of 21 days. Dietary treatments consisted of a basal diet (Control, no fat supplement) and the basal diet supplemented with SO (2.7% of dry matter (DM)) or HPO (2.7% of DM). Ruminal digesta pH, NH3-N and volatile fatty acids were not affected by dietary treatments. Compared with control and HPO, total bacteria measured as copies of 16S ribosomal DNA/ml by quantitative PCR was decreased (P<0.05) by SO. Fibrobacter succinogenes, Butyrivibrio proteoclasticus and Anaerovibrio lipolytica loads were not affected by dietary treatments. In contrast, compared with control, load of Prevotella bryantii was increased (P<0.05) with HPO diet. Compared with control and SO, HPO decreased (P<0.05) C18:2 cis n-6 in ruminal digesta. Contents of C15:0 iso, C18:11 trans-11 and C18:2 cis-9, trans-11 were increased (P<0.05) in ruminal digesta by SO compared with control and HPO. In conclusion, supplementation of SO or HPO do not affect ruminal fermentation parameters, whereas HPO can increase load of ruminal P. bryantii. Also, results observed in our targeted bacteria may have depended on the saturation degree of dietary oils.


Evaluation of Oxacillin and Cefoxitin Disk and MIC Breakpoints for Prediction of Methicillin Resistance in Human and Veterinary Isolates of Staphylococcus intermedius Group.
Staphylococcus pseudintermedius is a coagulase-positive species that colonizes the nares and anal mucosa of healthy dogs and cats. Human infections with S. pseudintermedius range in severity from bite wounds and rhinosinusitis to endocarditis; historically, these infections were thought to be uncommon, but new laboratory methods suggest that their true incidence is underreported. Oxacillin and cefoxitin disk and MIC tests were evaluated for the detection of mecA- or mecC-mediated methicillin resistance in 115 human and animal isolates of the Staphylococcus intermedius group (SIG), including 111 Staphylococcus pseudintermediusand 4 Staphylococcus delphini isolates, 37 of which were mecA positive. The disk and MIC breakpoints evaluated included the Clinical and Laboratory Standards Institute (CLSI) M100-S25 Staphylococcus aureus/Staphylococcus lugdunensis oxacillin MIC breakpoints and cefoxitin disk and MIC breakpoints, the CLSI M100-S25 coagulase-negative Staphylococcus (CoNS) oxacillin MIC breakpoint and cefoxitin disk breakpoint, the CLSI VET01-S2 S. pseudintermedius oxacillin MIC and disk breakpoints, and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) S. pseudintermedius cefoxitin disk breakpoint. The oxacillin results interpreted by the VET01-S2 (disk and MIC) and M100-S25 CoNS (MIC) breakpoints agreed with the results of mecA/mecC PCR for all isolates, with the exception of one false-resistant result (1.3% of mecA/mecC PCR-negative isolates). In contrast, cefoxitin tests performed poorly, ranging from 3 to 89% false susceptibility (very major errors) and 0 to 48% false resistance (major errors). BD Phoenix, bioMérieux Vitek 2, and Beckman Coulter MicroScan commercial automated susceptibility test panel oxacillin MIC results were also evaluated and demonstrated >95% categorical agreement with mecA/mecC PCR results if interpreted by using the M100-S25 CoNS breakpoint. The Alere penicillin-binding protein 2a test accurately detected all mecA-positive isolates, although for four isolates, cefoxitin induction was required prior to testing. These data demonstrate that the cefoxitin surrogate test does not reliably detect the presence of mecA in S. pseudintermedius isolates and that laboratories should perform oxacillin disk or MIC tests of these isolates when they are encountered.


Surface- and tip-enhanced Raman spectroscopy reveals spin-waves in iron oxide nanoparticles.
Nanomaterials have the remarkable characteristic of displaying physical properties different from their bulk counterparts. An additional degree of complexity and functionality arises when oxide nanoparticles interact with metallic nanostructures. In this context the Raman spectra due to plasmonic enhancement of iron oxide nanocrystals are here reported showing the activation of spin-waves. Iron oxide nanoparticles on gold and silver tips are found to display a band around 1584 cm(-1) attributed to a spin-wave magnon mode. This magnon mode is not observed for nanoparticles deposited on silicon (111) or on glass substrates. Metal-nanoparticle interaction and the strongly localized electromagnetic field contribute to the appearance of this mode. The localized excitation that generates this mode is confirmed by tip-enhanced Raman spectroscopy (TERS). The appearance of the spin-waves only when the TERS tip is in close proximity to a nanocrystal edge suggests that the coupling of a localized plasmon with spin-waves arises due to broken symmetry at the nanoparticle border and the additional electric field confinement. Beyond phonon confinement effects previously reported in similar systems, this work offers significant insights on the plasmon-assisted generation and detection of spin-waves optically induced.


Closed equation for the normal incidence reflectance of thin films on absorbing substrates.
The optical constants of thin films can be obtained from inversion of spectrophotometric measurements by using minimization gradient methods. The computational approach of these minimization methods requires closed compact formulas for reflectance and/or transmittance. For normal incidence closed compact formulations for the direct transmittance, both for thin films on transparent or absorbing substrates, and for the reflectance of thin films on transparent substrates, are available in the literature. We report here a closed compact formula to evaluate reflectance spectra of thin films on absorbing substrates, and it is shown that for vanishing substrate absorption this new, to the best of our knowledge, approach gives the same results obtained from the formulation corresponding to thin films supported by transparent substrates.


Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome.
The first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or pyridoxal 5'-phosphate and many of them showed residual enzyme activity. One sequence change (R116Q), predicted to affect flavin mononucleotide binding and binding of the two PNPO dimers, and with high residual activity was found in Groups (ii) and (iii). This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy.


Glutamate, aspartate and nucleotide transporters in the SLC17 family form four main phylogenetic clusters: evolution and tissue expression.
The SLC17 family of transporters transports the amino acids: glutamate and aspartate, and, as shown recently, also nucleotides. Vesicular glutamate transporters are found in distinct species, such as C. elegans, but the evolutionary origin of most of the genes in this family has been obscure. Our phylogenetic analysis shows that the SLC17 family consists of four main phylogenetic clades which were all present before the divergence of the insect lineage. One of these clades has not been previously described and it is not found in vertebrates. The clade containing Slc17a9 had the most restricted evolutionary history with only one member in most species. We detected expression of Slc17a1-17a4 only in the peripheral tissues but not in the CNS, while Slc17a5- Slc17a9 are highly expressed in both the CNS and periphery. The in situ hybridization studies on vesicular nucleotide transporter revealed high expression throughout the cerebral cortex, certain areas in the hippocampus and in specific nuclei of the hypothalamus and thalamus. Some of the regions with high expression, such as the medial habenula and the dentate gyrus of the hippocampus, are important sites for purinergic neurotransmission. Noteworthy, other areas relying on purine-mediated signaling, such as the molecular layer of the dentate gyrus and the periaqueductal gray, lack or have a very low expression of Slc17a9, suggesting that there could be another nucleotide transporter in these regions.


Assessing individual metabolic responsiveness to a lipid challenge using a targeted metabolomic approach.
The development of assessment techniques with immediate clinical applicability is a priority for resolving the growing epidemic in metabolic disease. Many imbalances in diet-dependent metabolism are not detectable in the fasted state. Resolving the high inter-individual variability in response to diet requires the development of techniques that can detect metabolic dysfunction at the level of the individual. The intra- and inter-individual variation in lipid metabolism in response to a standardized test meal was determined. Following an overnight fast on three different days, three healthy subjects consumed a test meal containing 40% of their daily calories. Plasma samples were collected at fasting, and 1, 3, 6, and 8 h after the test meal. Plasma fatty acid (FA) concentrations within separated lipid classes and lipoprotein fractions were measured at each time point. The intra-individual variation within each subject across three days was lower than the inter-individual differences among the three subjects for over 50% of metabolites in the triacylglycerol (TG), FA, and phosphatidylcholine (PC) lipid classes at 6 h, and for 25-50% of metabolites across lipid classes at 0, 1, 3, and 8 h. The consistency of response within individuals was visualized by principal component analysis (PCA) and confirmed by ANOVA. Three representative metabolites that discriminated among the three individuals in the apolipoprotein B (ApoB) fraction, TG16:1n7, TG18:2n6, and PC18:3n3, are discussed in detail. The postprandial responses of individuals were unique within metabolites that were individual discriminators (ID) of metabolic phenotype. This study shows that the targeted metabolomic measurement of individual metabolic phenotype in response to a specially formulated lipid challenge is possible even without lead-in periods, dietary and lifestyle control, or intervention over a 3-month period in healthy free-living individuals.


Clinical evaluation of two consecutive UroVysion fluorescence in situ hybridization tests to detect intravesical recurrence of bladder cancer: a prospective blinded comparative study in Japan.
We evaluated the use of UroVysion fluorescence in situ hybridization tests to detect the intravesical recurrence of bladder cancer during follow-up after a transurethral resection of bladder tumor (TURBT). In this prospective, blinded, comparative study, 486 patients treated by TURBT within the prior 2 years were registered at 12 centers. Urine cytology and UroVysion tests were performed once or twice at a central testing laboratory. For the patients with no suspicious findings of bladder cancer in the first analysis, the same examination set was repeated 3 months later as the second analysis. Totals of 468 and 399 patients were eligible for the first and second analyses, respectively. We determined the sensitivity and specificity of two consecutive UroVysion tests. Bladder cancers were identified in 44 patients at the first analysis. The UroVysion test had 50.0% (95% CI 35.2-64.8%) sensitivity and 72.4% (68.3-76.8%). Urine cytology had 4.5% (0.0-10.7%) sensitivity and 99.8% (99.3-100.0%) specificity. The concordant rate of the first and second UroVysion test results was 72% (kappa coefficient 0.157). Interestingly, the patients with two consecutive positive UroVysion test results had the highest cancer detection rate (14.8%), which is greater than those of the patients with a positive result in either (7.2%) or neither (1.2%) of the two tests at the 3-month follow-up. The UroVysion test provided higher sensitivity than urine cytology to detect bladder cancer during post-TURBT follow-up. Two consecutive UroVysion tests might be a better indicator to predict intravesical recurrence.


Validation of the integration of HIV and AIDS related nursing competencies into the undergraduate nursing curriculum in South Africa.
Being in its fourth decade, HIV remains an epidemic that requires combined efforts for the global fight. The strategies planned and implemented in the fight against HIV include reversing and halting the spread of HIV, increasing health care access, and strengthening the health care system. South Africa has made the fight one of its top priorities, and has developed plans to increase the role of nurses in the management of HIV, demonstrating its willingness, commitment and progress in the fight against HIV. This article presents the validation process conducted to confirm the integration and mapping of the HIV and AIDS related nursing competencies into the four-year Bachelor of Nursing programme at a university in South Africa. This study adopted a constructivist paradigm, using a qualitative approach, applyingthe design step of the process model of curriculum development, to validate the inte gration of the mapped HIV and AIDS related nursing competencies into the undergraduate nursing curriculum. For each competency, outcomes were developed for each year. Participants confirmed completeness of outcomes and appropriateness of the mapping of the HIV and AIDS related outcomes into the nursing curriculum, as well as the feasibility and practicability of the integration. Required resources for integration of HIV and AIDS related nursing competencies, such as human resources and nurse educators' continued personal development were identified, as well as barriers to integration, and measures to eliminate them were discussed. The importance of integration of HIV and AIDS nursing competencies into the curriculum was reiterated.


Data-driven multiscale modeling reveals the role of metabolic coupling for the spatio-temporal growth dynamics of yeast colonies.
Multicellular entities like mammalian tissues or microbial biofilms typically exhibit complex spatial arrangements that are adapted to their specific functions or environments. These structures result from intercellular signaling as well as from the interaction with the environment that allow cells of the same genotype to differentiate into well-organized communities of diversified cells. Despite its importance, our understanding how this cell-cell and metabolic coupling lead to functionally optimized structures is still limited. Here, we present a data-driven spatial framework to computationally investigate the development of yeast colonies as such a multicellular structure in dependence on metabolic capacity. For this purpose, we first developed and parameterized a dynamic cell state and growth model for yeast based on on experimental data from homogeneous liquid media conditions. The inferred model is subsequently used in a spatially coarse-grained model for colony development to investigate the effect of metabolic coupling by calibrating spatial parameters from experimental time-course data of colony growth using state-of-the-art statistical techniques for model uncertainty and parameter estimations. The model is finally validated by independent experimental data of an alternative yeast strain with distinct metabolic characteristics and illustrates the impact of metabolic coupling for structure formation. We introduce a novel model for yeast colony formation, present a statistical methodology for model calibration in a data-driven manner, and demonstrate how the established model can be used to generate predictions across scales by validation against independent measurements of genetically distinct yeast strains.


Laminar distribution of the pathological changes in frontal and temporal cortex in 8 patients with progressive supranuclear palsy.
To determine the laminar distribution of the pathological changes in the cerebral cortex in progressive supranuclear palsy (PSP). The distribution of the abnormally enlarged neurons (EN), surviving neurons, neurofibrillary tangles (NFT), glial inclusions (GI), tufted astrocytes (TA), and neuritic plaques (NP) were studied across the cortex in tau immunolabeled sections of frontal and temporal cortex in 8 cases of PSP. The distribution of the NFT was highly variable with no consistent pattern of laminar distribution. The GI were distributed either in the lower laminae or uniformly across the cortex. Surviving neurons exhibited either a density peak in the upper laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. The EN and glial cell nuclei were distributed primarily in the lower cortical laminae. There were positive correlations between the densities of the EN and glial cell nuclei and negative correlations between the surviving neurons and glial cells. No correlations were present between the densities of the NFT and GI. Cortical pathology in PSP predominantly affects the lower laminae but may spread to affect the upper laminae in some cases. The NFT and GI may have different laminar distributions and gliosis occurs concurrently with neuronal enlargement.


Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder.
Although lithium has been the most commonly used maintenance treatment in bipolar disorder for several decades, valproate is being used increasingly - especially in the United States of America. There is a need to clarify whether the increasingly prominent prophylactic role of valproate in bipolar disorder is justified. To review the effectiveness of valproate, relative to placebo, other mood stabilisers and antipsychotics, in the prevention and/or attenuation of acute episodes of bipolar disorder. The effectiveness of valproate was considered in terms of mood symptoms, mortality, general health, social functioning, adverse effects and overall acceptability to patients. The CCDAN group search strategy was used. The following databases were searched: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), The Cochrane Controlled Clinical Trials Register (CCCTR), EMBASE, MEDLINE, LILACS, PsycLIT and Psyndex. Reference lists of relevant papers and major textbooks of mood disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable published or unpublished trials. Randomised controlled trials which compared valproate with placebo, alternative mood stabilisers (including lithium and carbamazepine) or neuroleptics, where the stated intent of intervention was the maintenance treatment of bipolar disorder. Participants were males and females of all ages with a diagnosis of bipolar disorder however diagnosed, approximating to ICD 10 Code F31 and DSM IV 296, but including patients diagnosed as ICD-9 manic depressive psychosis and DSM-III and DSM-IIIR bipolar disorder. Data were extracted from the original reports individually by two reviewers. The main outcomes to be assessed were: 1. The effectiveness of valproate treatment in preventing or attenuating further episodes of bipolar disorder, including its effectiveness in rapid cycling disorder. 2. The acceptability of valproate treatment to patients. 3. The prevalence of side-effects. 4. Mortality on valproate treatment. Outcomes concerning relapse/recurrence were analysed excluding data from discontinuation studies, which were to be analysed separately. Sub-group analyses were to be performed to examine the effects of valproate treatment in rapid cycling bipolar disorder and previous mood stabiliser non-responders. Data were analysed using Review Manager version 4.1. One trial of 12 months duration with 372 participants was identified comparing lithium, divalproex and placebo. It had several methodological limitations. The primary analysis of time to occurrence of mood episode described in the main trial report found no reliable difference between the treatments, although there was a trend for divalproex to be more effective than lithium. In the analysis in this review, patients taking divalproex who left the study because of the occurrence of an mood episode were significantly less in number than those on placebo (RRR 37%; RR 0.63; 95% CI 0.44 to 0.90). There was no significant difference in the numbers of patients in receipt of divalproex compared with those in receipt of lithium who left the study because they suffered any mood episode. (RRR 22%; RR 0.78; 95% C.I. 0.52 to 1.17). There was insufficient information to allow sub-group analyses of rapid-cycling disorder. The divalproex group had significantly more patients suffering tremor (RRI 223%; RR 3.23; 95% C.I. 1.85 to 5.62), weight gain (RRI 187%; RR 2.87; 95% C.I. 1.34 to 6.17) and alopecia (RRI 143%; RR 2.43; 95% C.I. 1.05 to 5.65) than the placebo group. In comparison with the lithium, divalproex was associated with more frequent sedation (RRI 58%; RR 1.58; 95% C.I. 1.08 to 2.32) and infection (RRI 107%; RR 2.07; 95% C.I. 1.16 to 3.68), but less suffered thirst (RRR 62%; RR 0.38; 95% C.I. 0.18 to 0.81) and polyuria (RRR 57%; RR 0.43; 95% C.I. 0.22 to 0.82). In view of the equivocal findings of this review, conclusions about the efficacy and acceptability of valproate compared to placebo and lithium cannot be made with any degree of confidence. With current evidence, patients and clinicians would probably wish to use lithium before valproate for maintenance treatment. At present, the observed shift of prescribing practice to valproate is not based on reliable evidence of efficacy


Neuronal controls of a behavioral response mediated by the abdominal ganglion of Aplysia.
Tactile stimulation of the siphon and mantle shelf in Aplysia causes a characteristic withdrawal response of the external organs of the mantle cavity. A similar response also occurs spontaneously. Both responses are mediated by the abdominal ganglion and therefore provide an opportunity for correlating cellular functioning and behavior in a relatively simple and well-studied neuronal system. The withdrawal responses are controlled by five identified motor cells which receive two types of synaptic inputs. One set of excitatory connections, activated by tactile stimulation of the siphon and mantle shelf, mediates the defensive withdrawal reflex. A second set of connections is activated by a spontaneous burst of activity in a group of closely coupled interneurons which are excitatory to some of the motor cells and inhibitory to the others. This second set of connections mediates the spontaneous withdrawal response. These two inputs can therefore switch the same population of motor cells from a simple reflex to a more complex, internally organized response.


Vibronic coupling in organic semiconductors for photovoltaics.
Light-induced charge transfer from the photoexcited donor to the acceptor is the fundamental step towards current generation in organic solar cells. Experimental evidence for efficient charge separation on ultrafast time scales has been available for quite some time. Yet even today, the elementary mechanisms underlying this process in organic semiconductors and in particular the role of the coherent wave-like motion of electrons and nuclei for the charge separation are still a matter of considerable debate. In this perspective, we present a survey of the current understanding on the role of quantum coherences in organic semiconductors. Specifically, we discuss the role of vibronic couplings for ultrafast charge separation dynamics with particular attention on the potential implications for the light-to-current conversion process in photovoltaic devices.


Dopaminergic modulation of corticostriatal responses in medium spiny projection neurons from direct and indirect pathways.
Suprathreshold corticostriatal responses recorded from medium spiny neurons (MSNs) from the direct and indirect pathways of the basal ganglia are different. Their differences readily distinguish D(1)- and D(2)-type receptor expressing MSNs in both bacterial artificial chromosome-transgenic mice and their control littermates as well as in rats: indirect pathway neurons are more excitable than direct pathway neurons revealing autoregenerative spikes underlying their spike trains, whereas direct pathway neurons exhibit more prolonged plateau potentials and spike trains. SFK 81297, a selective agonist for D(1)-class receptors enhanced corticostriatal responses in direct pathway neurons, while quinelorane, a selective agonist for D(2)-class receptors reduced orthodromic and autoregenerative responses in indirect pathway neurons thus making both neuron classes similarly excitable. Because dopaminergic postsynaptic actions target Ca(V)1 (L) class voltage-gated calcium channels in MSNs, we hypothesized that these channels are involved and can explain a part of the dopaminergic actions on corticostriatal integration. Both 2.5 μM nicardipine and 400 nM calciseptine, selective Ca(V)1 channel blockers, reduced corticostriatal responses in both D(1)- and D(2)-receptor expressing neurons, respectively. A previous blockade of Ca(V)1 channels occluded the actions of dopamine agonists in both neuronal classes. In contrast, a Ca(V)1 (L) channel activator, 2.5 μM Bay K 8644, enhanced corticostriatal responses in neurons from both pathways. It is concluded that Ca(V)1 intrinsic currents mediate a part of the dopaminergic modulation during orthodromic synaptic integration of cortical inputs in both classes of MSNs.


Rye polyphenols and the metabolism of n-3 fatty acids in rats: a dose dependent fatty fish-like effect.
As long-chain fatty acids (LCFA) of the n-3 series are critically important for human health, fish consumption has considerably increased in recent decades, resulting in overfishing to respond to the worldwide demand, to an extent that is not sustainable for consumers' health, fisheries economy, and marine ecology. In a recent study, it has been shown that whole rye (WR) consumption improves blood and liver n-3 LCFA levels and gut microbiota composition in rats compared to refined rye. The present work demonstrates that specific colonic polyphenol metabolites may dose dependently stimulate the synthesis of n-3 LCFA, possibly through their microbial and hepatic metabolites in rats. The intake of plant n-3 alpha-linolenic acid and WR results in a sort of fatty fish-like effect, demonstrating that the n-3 LCFA levels in blood and tissues could be increased without eating marine foods, and therefore without promoting unsustainable overfishing, and without damaging marine ecology.


A 2.4-GHz Energy-Efficient Transmitter for Wireless Medical Applications.
A 2.4-GHz energy-efficient transmitter (TX) for wireless medical applications is presented in this paper. It consists of four blocks: a phase-locked loop (PLL) synthesizer with a direct frequency presetting technique, a class-B power amplifier, a digital processor, and nonvolatile memory (NVM). The frequency presetting technique can accurately preset the carrier frequency of the voltage-controlled oscillator and reduce the lock-in time of the PLL synthesizer, further increasing the data rate of communication with low power consumption. The digital processor automatically compensates preset frequency variation with process, voltage, and temperature. The NVM stores the presetting signals and calibration data so that the TX can avoid the repetitive calibration process and save the energy in practical applications. The design is implemented in 0.18- μm radio-frequency complementary metal-oxide semiconductor process and the active area is 1.3 mm (2). The TX achieves 0-dBm output power with a maximum data rate of 4 Mb/s/2 Mb/s and dissipates 2.7-mA/5.4-mA current from a 1.8-V power supply for on-off keying/frequency-shift keying modulation, respectively. The corresponding energy efficiency is 1.2 nJ/b·mW and 4.8 nJ/b· mW when normalized to the transmitting power.


Novel insights into Sabino1 and splashed white coat color patterns in horses.
Within the framework of genome-wide analyses using the novel Axiom® genotyping array, we investigated the distribution of two previously described coat color patterns, namely sabino1 (SBI), associated with the KIT gene (KI16+1037A), and splashed white, associated with the PAX3 gene (ECA6:g.11429753C>T; PAX3C70Y ), including a total of 899 horses originating from eight different breeds (Achal Theke, Purebred Arabian, Partbred Arabian, Anglo-Arabian, Shagya Arabian, Haflinger, Lipizzan and Noriker). Based on the data we collected we were able to demonstrate that, besides Quarter horses, the PAX3C70Y allele is also present in Noriker (seven out of 189) and Lipizzan (three out of 329) horses. The SB1 allele was present in three breeds (Haflinger, 14 out of 98; Noriker, four out of 189; Lipizzan one out of 329). Furthermore, we examined the phenotypes of SB1- and PAX3C70Y -carrier horses for their characteristic white spotting patterns. None of the SB1/sb1-carrier horses met the criteria defining the Sabino1 pattern according to current applied protocols. From 10 heterozygous PAX3C70Y -carrier horses, two had nearly a splashed white phenotype. The results of this large-scale experiment on the genetic association of white spotting patterns in horses underline the influence of gene interactions and population differences on complex traits such as Sabino1 and splashed white.


The Interaction of Smoking with Gene Polymorphisms on Four Digestive Cancers: A Systematic Review and Meta-Analysis.
The main purpose of this study was to perform a meta-analysis to assess the interaction between smoking and nine genes (GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, SULT1A1, hOGG1, XRCC1 and p53) on colorectal cancer, gastric cancer, liver cancer and oesophageal cancer. Published articles from the PubMed, ISI and EMBASE databases were retrieved. A total of 67 case-control studies or nested case-control studies were identified for the analysis. The pooled jodds ratio (OR) with 95% confidence interval (CI) was calculated using the random effect model. The overall study showed that the GSTM1 polymorphism was associated with the risk of the four digestive cancers among Asian population (OR 1.284, 95% CI: 1.122-1.470, p: 0). Subgroup analyses by cancer site showed that GSTM1 null genotype increased the gastric cancer risk in total population (OR 1.335, 95% CI: 1.145-1.556, p: 0). However, the association of GSTM1 null genotype with the oesophageal cancer risk was found in smokers (OR 1.382, 95% CI: 1.009-1.894, p:0.044), but not in non-smokers (OR 1.250, 95% CI: 0.826-1.891, p:0.290). Moreover, smokers with the CYP1A1 IIe462Val polymorphism were at an increased cancer risk in Asian population (OR=1.585, 95% CI 1.029-2.442, p: 0.037). None of the other gene-smoking interactions was observed in the above cancers. This meta-analysis reveals two potential gene-smoking interactions, one is between smoking and GSTM1 on oesophageal cancer, and the other is between smoking and CYP1A1 IIe462Val on the four cancers in Asian population. Future studies need to be conducted to verify the conclusions.


High-resolution lidar observations of mesospheric sodium and implications for adaptive optics.
Observations of sodium density variability in the upper mesosphere/lower thermosphere, obtained using a high-resolution lidar system, show rapid fluctuations in the sodium centroid altitude. The temporal power spectrum extends above 1 Hz and is well-fit by a power law having a slope that is -1.95±0.12. These fluctuations produce focus errors in adaptive optics systems employing continuous-wave sodium laser guide stars, which can be significant for large-aperture telescopes. For a 30 m aperture diameter, the associated rms wavefront error is approximately 4 nm per meter of altitude change and increases as the square of the aperture diameter. The vertical velocity of the sodium centroid altitude is found to be ~23 ms(-1) on a 1 s time scale. If these high-frequency fluctuations arise primarily from advection of horizontal structure by the mesospheric wind, our data imply that variations in the sodium centroid altitude on the order of tens of meters occur over the horizontal scales spanned by proposed laser guide star asterisms. This leads to substantial differential focus errors (~107 nm over a 1 arc min separation with a 30 m aperture diameter) that may impact the performance of wide-field adaptive optics systems. Short-lasting and narrow sodium density enhancements, more than 1 order of magnitude above the local sodium density, occur due to advection of meteor trails. These have the ability to change the sodium centroid altitude by as much as 1 km in less than 1 s, which could result in temporary disruption of adaptive optics systems.


Recombination and population structure in Salmonella enterica.
Salmonella enterica is a bacterial pathogen that causes enteric fever and gastroenteritis in humans and animals. Although its population structure was long described as clonal, based on high linkage disequilibrium between loci typed by enzyme electrophoresis, recent examination of gene sequences has revealed that recombination plays an important evolutionary role. We sequenced around 10% of the core genome of 114 isolates of enterica using a resequencing microarray. Application of two different analysis methods (Structure and ClonalFrame) to our genomic data allowed us to define five clear lineages within S. enterica subspecies enterica, one of which is five times older than the other four and two thirds of the age of the whole subspecies. We show that some of these lineages display more evidence of recombination than others. We also demonstrate that some level of sexual isolation exists between the lineages, so that recombination has occurred predominantly between members of the same lineage. This pattern of recombination is compatible with expectations from the previously described ecological structuring of the enterica population as well as mechanistic barriers to recombination observed in laboratory experiments. In spite of their relatively low level of genetic differentiation, these lineages might therefore represent incipient species.


The epidemiology and pathogenesis of osteoporosis.
Osteoporosis is an increasing health care concern as populations age throughout the developed and developing world. The social and economic costs of osteoporosis are due to its clinical outcome of fracture which increases exponentially with age. This review will highlight some of the key epidemiological aspects of osteoporosis incorporating areas of more recent interest. These include the definition; the magnitude of the problem encompassing differing incidence and prevalence patterns of both low bone mass and fracture in different cultural groups; the social consequences of fracture, including economic costs, morbidity and mortality; the evaluation of fracture risk, including the role of bone density, bone quality and the risk of falling; as well as an overview of some of the factors involved in determining low bone mass. Bone mineral density (BMD) is the most easily measured and accurate predictor of fracture risk. For any individual, BMD is the combination of their peak bone density and subsequent bone loss, both of which are influenced by genetic, hormonal and environmental factors. An understanding of key issues relating to this important disease may lead to earlier detection of the individual at high risk for fracture and rational approach to prevention and management.


Extra-arachnoidal cranio-cervical decompression for syringomyelia associated with Chiari I malformation in adults: technique assessment.
The osteo-dural decompression of the cerebellar tonsils at the cranio-cervical junction is generally considered the most effective treatment for syringomyelia-Chiari I complex. However much controversy concerning a great number of surgical adjuvants to the standard bony decompression is still present. In this work an extra-arachnoidal cranio-cervical decompression (CCD) without duroplasty is described and the surgical results are reported. Between 2000 and 2005, 24 adult patients underwent surgery for symptomatic syringomyelia-Chiari I complex not associated with hydrocephalus. In all cases, the surgical procedure consisted of a limited suboccipital craniectomy and laminectomy of C1 (when necessary C2 as well) followed by dural opening leaving the arachnoid membrane intact. The dura mater is left open and stitched laterally to the muscles. With a mean clinical long term follow-up of 44 months (range, 12-78 mo), neurological disturbances improved in 21 of 24 patients (87.5%) as result of extra-arachnoidal CCD. The postoperative complications occurred when the arachnoid was accidentally violated (4 cases, 16.6%). The complications included aseptic meningitis (one patient), nucal pseudomeningocele (two patients) and postoperative hydrocephalus requiring a ventriculoperitoneal shunt (one patient). Finally, one patient received an additional C2 laminectomy in order to obtain symptoms improvement and syrinx shrinkage. Postoperative MRI studies demonstrated that the syrinx decreased in size or collapsed in 20 patients (83.3%) and stabilized in 4 (16.7%). The extra-arachnoidal CCD is a safe and effective treatment for syringomyelia associated with Chiari I malformation in adults without intraoperative evidence of adhesive arachnoiditis. However a larger number of patients and longer follow-up will be necessary to determine the efficacy of extra-arachnoidal CCD.


Perceived swallowing problems and mortality risk in very elderly people ≥85 years old: Results of the Tokyo Oldest Old Survey on Total Health study.
The aim of this study was to clarify whether perceived swallowing problems affect the life expectancy of very elderly individuals. In an ageing society, oral function affects health status. In particular, a decline in swallowing function may increase the risk of various diseases, morbidity and malnutrition. We evaluated 526 elderly individuals aged ≥85 years. All participants completed a questionnaire and underwent oral, physical and mental health examinations. The comprehensive oral health assessment comprised a face-to-face interview that included a questionnaire on swallowing function. We estimated hazard ratios and 95% confidence intervals using the Cox proportional hazards model, adjusting for potential confounders between perceived swallowing problems and all-cause mortality over a 3-year period. Over a 3-year follow-up period, 88 of 526 participants died and 68 participants complained of perceived swallowing problems. Perceived swallowing problems had statistically significant associations with physical status and function and nutrition. In the univariate analysis, perceived swallowing problems had statistically significant associations with an approximately 1.9-fold higher risk of all-cause mortality during the 3-year period (HR: 1.89, 95% CI: 1.14-3.14). In the multivariate analysis, the statistically significant association between perceived swallowing problems and all-cause mortality remained after adjusting for various confounding factors (HR: 1.73, 95% CI: 1.03-2.92). Perceived swallowing disorders should be verified by a clinical examination, as they are associated with other health outcomes and increased all-cause mortality.


Target gene analysis by microarrays and chromatin immunoprecipitation identifies HEY proteins as highly redundant bHLH repressors.
HEY bHLH transcription factors have been shown to regulate multiple key steps in cardiovascular development. They can be induced by activated NOTCH receptors, but other upstream stimuli mediated by TGFß and BMP receptors may elicit a similar response. While the basic and helix-loop-helix domains exhibit strong similarity, large parts of the proteins are still unique and may serve divergent functions. The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells. We therefore sought to identify target genes for HEY proteins by microarray expression and ChIPseq analyses in HEK293 cells, cardiomyocytes, and murine hearts. HEY proteins were found to modulate expression of their target gene to a rather limited extent, but with striking functional interchangeability between HEY factors. Chromatin immunoprecipitation revealed a much greater number of potential binding sites that again largely overlap between HEY factors. Binding sites are clustered in the proximal promoter region especially of transcriptional regulators or developmental control genes. Multiple lines of evidence suggest that HEY proteins primarily act as direct transcriptional repressors, while gene activation seems to be due to secondary or indirect effects. Mutagenesis of putative DNA binding residues supports the notion of direct DNA binding. While class B E-box sequences (CACGYG) clearly represent preferred target sequences, there must be additional and more loosely defined modes of DNA binding since many of the target promoters that are efficiently bound by HEY proteins do not contain an E-box motif. These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression.


This is your new normal: A qualitative study of barriers and facilitators to physical activity in Veterans with lower extremity loss.
Regular physical activity (PA) is essential for aging well with a disability, preventing the onset or worsening of chronic conditions, functional loss, and maintaining or improving quality of life, yet PA levels are low in those with disabilities, including those with a lower extremity amputation (LEA). To determine methods for promoting PA in this population, our objective was to better understand the barriers and facilitators to PA that persons with LEA face. Semi-structured interviews were conducted with male Veterans with a LEA. Two raters analyzed interview transcripts using a qualitative descriptive approach, involving both a priori and emergent themes. Among the 27 male Veterans (mean age = 54 years) interviewed, facilitators to PA included acceptance of their limb loss, confidence (to try new activities or adapt activities), creating a daily routine involving PA, resources, supportive others, perceived benefit, and having a history of being physically active. Barriers to PA were illnesses/injuries, poorly-fitting prostheses, low self-efficacy, insufficient resources, unsupportive others, and hassle. Our study builds upon the literature indicating that individual, interpersonal, and environmental factors should be addressed to increase adoption and maintenance of PA, including making PA a regular, low-hassle activity, increasing access to resources that facilitate PA, and training health care providers, family and friends on how to best to support those with LEA to be more physically active. Addressing prosthetic socket issues that affect fit and stability and promoting acceptance and self-efficacy will also be instrumental.


Blockchain-Based Security Mechanisms for IoMT Edge Networks in IoMT-Based Healthcare Monitoring Systems.
Despite the significant benefits that the rise of Internet of Medical Things (IoMT) can bring into citizens' quality of life by enabling IoMT-based healthcare monitoring systems, there is an urgent need for novel security mechanisms to address the pressing security challenges of IoMT edge networks in an effective and efficient manner before they gain the trust of all involved stakeholders and reach their full potential in the market of next generation IoMT-based healthcare monitoring systems. In this context, blockchain technology has been foreseen by the industry and research community as a disruptive technology that can be integrated into novel security solutions for IoMT edge networks, as it can play a significant role in securing IoMT devices and resisting unauthorized access during data transmission (i.e., tamper-proof transmission of medical data). However, despite the fact that several blockchain-based security mechanisms have already been proposed in the literature for different types of IoT edge networks, there is a lack of blockchain-based security mechanisms for IoMT edge networks, and thus more effort is required to be put on the design and development of security mechanisms relying on blockchain technology for such networks. Towards this direction, the first step is the comprehensive understanding of the following two types of blockchain-based security mechanisms: (a) the very few existing ones specifically designed for IoMT edge networks, and (b) those designed for other types of IoT networks but could be possibly adopted in IoMT edge networks due to similar capabilities and technical characteristics. Therefore, in this paper, we review the state-of-the-art of the above two types of blockchain-based security mechanisms in order to provide a foundation for organizing research efforts towards the design and development of reliable blockchain-based countermeasures, addressing the pressing security challenges of IoMT edge networks in an effective and efficient manner.


Sustained delivery by leucine-modified chitosan spray-dried respirable powders.
The controlled co-delivery of multiple agents to the lung offers potential benefits to patients. This study investigated the preparation and characterisation of highly respirable spray-dried powders displaying the sustained release of two chemically distinct therapeutic agents. Spray-dried powders were produced from 30% (v/v) aqueous ethanol formulations that contained hydrophilic (terbutaline sulphate) and hydrophobic (beclometasone dipropionate) model drugs, chitosan (as a drug release modifier) and leucine (aerosolisation enhancer). The influence of chitosan molecular weight on spray-drying thermal efficiency, aerosol performance and drug release profile was investigated. Resultant powders were physically characterised: with in vitro aerosolisation performance and drug release profile investigated by the Multi-Stage Liquid Impinger and modified USP II dissolution apparatus, respectively. It was found that increased chitosan molecular weight gave increased spray-drying thermal efficiency. The powders generated were of a suitable size for inhalation-with emitted doses over 90% and fine particle fractions up to 72% of the loaded dose. Sustained drug release profiles were observed in dissolution tests for both agents: increased chitosan molecular weight associated with increased duration of drug release. The controlled co-delivery of hydrophilic and hydrophobic entities underlines the capability of spray drying to produce respirable particles with sustained release for delivery to the lung.


Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia.
Iron maldistribution has been implicated in multiple diseases, including the anemia of inflammation (AI), atherosclerosis, diabetes, and neurodegenerative disorders. Iron metabolism is controlled by hepcidin, a 25-amino acid peptide. Hepcidin is induced by inflammation, causes iron to be sequestered, and thus, potentially contributes to AI. Human hepcidin (hHepc) overexpression in mice caused an iron-deficient phenotype, including stunted growth, hair loss, and iron-deficient erythropoiesis. It also caused resistance to supraphysiologic levels of erythropoiesis-stimulating agent, supporting the hypothesis that hepcidin may influence response to treatment in AI. To explore the role of hepcidin in inflammatory anemia, a mouse AI model was developed with heat-killed Brucella abortus treatment. Suppression of hepcidin mRNA was a successful anemia treatment in this model. High-affinity antibodies specific for hHepc were generated, and hHepc knock-in mice were produced to enable antibody testing. Antibody treatment neutralized hHepc in vitro and in vivo and facilitated anemia treatment in hHepc knock-in mice with AI. These data indicate that antihepcidin antibodies may be an effective treatment for patients with inflammatory anemia. The ability to manipulate iron metabolism in vivo may also allow investigation of the role of iron in a number of other pathologic conditions.


Fertility intentions and interest in integrated family planning services among women living with HIV in Nyanza Province, Kenya: a qualitative study.
Despite increasing efforts to address the reproductive health needs of people living with HIV, a high unmet need for contraception exists among HIV+ women in sub-Saharan Africa. This study explores the fertility intentions and family planning (FP) preferences of Kenyan women accessing HIV treatment. We conducted 30 semistructured interviews and qualitatively analyzed the data with a grounded theory approach. Fears of premature death, financial hardship, and perinatal HIV transmission emerged as reasons for participants' desire to delay/cease childbearing. Participants strongly identified FP needs, yet two-thirds were using male condoms alone or no modern method of contraception. Women preferred the HIV clinic as the site of FP access for reasons of convenience, provider expertise, and a sense of belonging, though some had privacy concerns. Our findings support the acceptability of integrated FP and HIV services. Efforts to empower women living with HIV to prevent unintended pregnancies must expand access to contraceptive methods, provide confidential services, and take into account women's varied reproductive intentions.


Recent care of common mental disorders in the United States : prevalence and conformance with evidence-based recommendations.
To relate the presence of recent mental disorders to use of mental health services. Cross-sectional survey. The study population was 3,032 respondents to the Midlife Development in the United States (MIDUS) survey, a nationally representative telephone-and-mail survey conducted in 1996. Twelve-month diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders, Revised, Third Edition, of major depressive episode, panic disorder, generalized anxiety disorder, and serious mental illness were made using a structured assessment. Information was obtained on 12-month treatment for mental health problems in the general medical, mental health specialty, human services, and self-help sectors. Definitions of treatments consistent with evidence-based recommendations were developed using available practice guidelines. Crude and adjusted likelihoods of receiving any mental health care and guideline-concordant care were measured. Although 53. 8% of respondents with at least one 12-month mental disorder received any mental health care in the previous year, only 14.3% received care that could be considered consistent with evidence-based treatment recommendations. Even among those with the most serious and impairing mental illness, only 25% received guideline-concordant treatment. Predictors of receiving guideline-concordant care included being white, female, severely ill, and having mental health insurance coverage. An epidemic of untreated and poorly treated mental disorders exists in the United States, especially among vulnerable groups such as African Americans and the underinsured. Cost-effective interventions are needed to improve both access to and quality of treatment.


Size-tunable microvortex capture of rare cells.
Inertial separation of particles and cells based on their size has advanced significantly over the last decade. However, size-based inertial separation methods require precise tuning of microfluidic device geometries to adjust the separation size of particles or cells. Here, we show a passive capture method that targets a wide size range of cells by controlling the flow conditions in a single device geometry. This multimodal capture device is designed to generate laminar vortices in lateral cavities that branch from long rectangular channels. Micro-vortices generated at lower Reynolds numbers capture and stabilize large particles in equilibrium orbits or limit cycles near the vortex core. Other smaller particles or cells orbit near the vortex boundaries and they are susceptible to exiting the cavity flow. In the same cavity, however, at higher Reynolds number, we observe small particles migrating inward. This evolution in limit cycle trajectories led to a corresponding evolution in the average size of captured particles, indicating that the outermost orbits are less stable. We identify three phases of capture as a function of Reynolds number that give rise to unique particle orbit trajectories. Flow-based switching overcomes a major engineering challenge to automate capture and release of polydisperse cell subpopulations. The approach can expand clinical applications of label free trapping in isolating and processing a larger subset of rare cells like circulating tumor cells (CTCs) from blood and other body fluids.